U.S. patent number 4,472,431 [Application Number 06/565,379] was granted by the patent office on 1984-09-18 for method for treatment of shock.
This patent grant is currently assigned to Methodist Hospital of Indiana, Inc.. Invention is credited to Phillip D. Toth.
United States Patent |
4,472,431 |
Toth |
September 18, 1984 |
Method for treatment of shock
Abstract
A method for the treatment of shock is disclosed which includes
the administration of a therapeutically effective amount of
fenoprofen, which may be administered either as a pretreatment or
subsequent to the onset of the shock condition. The fenoprofen is
preferably administered intravenously.
Inventors: |
Toth; Phillip D. (Lebanon,
IN) |
Assignee: |
Methodist Hospital of Indiana,
Inc. (Indianapolis, IN)
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Family
ID: |
27061503 |
Appl.
No.: |
06/565,379 |
Filed: |
December 27, 1983 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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524457 |
Aug 18, 1983 |
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Current U.S.
Class: |
514/570 |
Current CPC
Class: |
A61K
31/42 (20130101) |
Current International
Class: |
A61K
31/42 (20060101); A61K 031/19 () |
Field of
Search: |
;424/317 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Woodard, Weikart, Emhardt &
Naughton
Parent Case Text
RELATED APPLICATION
The present application is a continuation in part of my copending
U.S. patent application Ser. No. 524,457, filed on Aug. 18, 1983.
Claims
What I claim is:
1. A method for the treatment of shock which comprises
administering parenterally to a person suffering from shock a
therapeutically effective amount of fenoprofen.
2. The method of claim 1 in which the fenoprofen is administered
within two hours after onset of the shock condition.
3. The method of claim 1 in which the fenoprofen is administered
intravenously.
4. The method of claim 3 in which the fenoprofen is administered
within two hours after onset of the shock condition.
5. A method for the treatment of a person having a potential for
the onset of a shock condition, which method comprises
administering parenterally to the person having the potential for
the onset of shock a therapeutically effective amount of
fenoprofen.
6. The method of claim 5 in which the fenoprofen is administered to
a person having a high risk of the onset of shock.
7. The method of claim 5 in which the fenoprofen is administered to
a hospitalized patient.
8. The method of claim 7 in which the patient has a high risk of
the onset of shock.
9. The method of claim 5 in which the fenoprofen is administered to
a person who has recently suffered a significant loss of blood.
10. The method of claim 5 in which the fenoprofen is administered
to a person having a high risk of infection.
11. The method of claim 10 in which the person is a hospitalized
patient.
12. The method of claim 5 in which the fenoprofen is administered
to a hospitalized patient prior to the patient's undergoing a
surgical procedure.
13. The method of claim 12 in which the fenoprofen is administered
to the patient within an hour before the surgical procedure.
14. The method of claim 12 in which the surgical procedure subjects
the patient to a high risk of infection.
15. The method of claim 12 in which the surgical procedure subjects
the patient to a high risk of a significant blood loss.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention: The present invention relates to the
field of methods for the treatment of shock, and more particularly
to a method for treating shock by use of drugs.
2. Description of the Prior Art: The term shock is applied to a
variety of pathophysiological conditions associated with
hypotension. Shock is a condition of acute peripheral circulatory
failure due to derangement of circulatory control or loss of
circulating fluid and is marked by pallor and claminess of the
skin, decreased blood pressure, feeble rapid pulse, decreased
respiration, restlessness, anxiety, and sometimes unconsciousness.
Some examples are hemorrhagic shock (blood loss), cardiogenic shock
(heart attack), endotoxic shock, and septic shock (infection).
In spite of aggressive therapy, the morbidity and mortality rates
for shock patients are quite high, in the range of 20-70%.
Moreover, this has been a condition which has been extremely
difficult to treat. Much research has been conducted in this field
in an effort to determine the mechanism of the shock condition and
methodologies for satisfactory treatment of shock after its
onset.
There has been recent speculation that the body releases certain
hormones or mediators which cause the low blood pressure. Many
vasoactive mediators have been implicated in the pathophysiology of
many shock states including endotoxic shock. The mediators which
have received much attention in endotoxic shock have been the
opioids, prostanoids, histamine, kinins, serotonin, VIP, etc.
However, what has yet to be established is the relative hemodynamic
contribution of each of these mediators in a given shock model.
Some drugs are currently being promoted for use in the treatment of
shock. Previously, the use of a massive dose of glucocorticoids in
a patient with septic shock was being employed. The Food and Drug
Administration recently reviewed the indications for the use of
corticosteroids in septic shock, in particular for a drug
methylprednisolone sodium succinate, and decided to remove septic
shock from the product insert as an indication for the use of high
doses. The use of this and related drugs for the treatment of shock
is discussed in an article entitled "Septic Shock and
Corticosteroids", John N. Sheagren, M.D., appearing in The New
England Journal of Medicine, pp. 456-7, Aug. 20, 1981.
It has previously been demonstrated that the cyclo-oxygenase
inhibitor, ibuprofen, given 60 minutes after endotoxin
administration could improve hemodynamics but not survival over
control animals in a canine endotoxic shock model. A paper on this
subject entitled "The Effects of Different Vasoactive Mediator
Antagonists on Endotoxic Shock in Dogs I" was presented at the
Fifth Annual Conference on Shock, at Smugglers' Notch. Vt. on June
9-11, 1982.
A method for the treatment of shock is described in U.S. Pat. No.
4,267,182, issued to Holaday on May 12, 1981. This method includes
the administration to the patient of any of a number of drugs
including naloxone, naltrexone, nalorphine, diprenorphine,
levallorphan, pentazocine, metazocine, cyclazocine, etazocine and
the acid addition salts thereof. Each of these drugs is indicated
as a narcotic antagonist drug.
The present invention relates to the use of fenoprofen for the
treatment of shock. Fenoprofen is a known anti-inflammatory drug
which has been available from Eli Lilly & Co. of Indianapolis,
Ind. for use in the treatment of arthritis. Other anti-inflammatory
drugs and their use are described in U.S. Pat. Nos. 4,355,029,
issued to Ridolfo on Oct. 19, 1982; 4,282,214, isued to Flora on
Aug. 4, 1981; 4,185,100, issued to Marvel on Jan. 22, 1980;
4,142,054, issued to Amin on Feb. 27, 1979; 4,135,051, issued to
Walker on Jan. 16, 1979; and 4,107,439, issued to Salmond on Aug.
15, 1978.
Despite the research conducted in this field, there has remained a
strong need for a method for the treatment of shock to both improve
hemodynamics and survival. Although various drugs have been
investigated for this purpose, the results to date have not been
highly successful.
SUMMARY OF THE INVENTION
Briefly describing one aspect of the present invention there is
provided a method for the treatment of shock which includes
administering to the patient a therapeutically effective amount of
fenoprofen.
It is an object of the present invention to provide a method for
the treatment of shock.
It is a further object of the present invention to provide a method
for treating shock which is successful both in improving
hemodynamics and in overall recovery from the condition.
Another object of the present invention is to provide a method of
treating shock which is readily followed.
A further object of the present invention is to provide a method
for the treatment of shock either by pre-treatment or by treatment
late in the condition.
Further objects and advantages of the present invention will become
apparent from the description of the preferred embodiment which
follows.
DESCRIPTION OF THE PREFERRED EMBODIMENT
For the purposes of promoting an understanding of the principles of
the invention, reference will now be made to the preferred
embodiment and specific language will be used to describe the same.
It will nevertheless be understood that no limitation of the scope
of the invention is thereby intended, such alterations and further
modifications in the described process, and such further
applications of the principles of the invention as illustrated
therein being contemplated as would normally occur to one skilled
in the art to which the invention relates.
The present invention involves the treatment of shock by the
administration of fenoprofen in a therapeutically effective amount.
As will be indicated in the specific examples to follow, it has
been found that the administration of such drug has resulted in
both improved hemodynamics and increased survival. These results
evidence a remarkable impact of the use of this drug in the
treatment of a condition which has been a severe problem.
Fenoprofen is a drug which is known in the industry, and in the
past has been indicated primarily for its efficacy as an
anti-inflammatory. This drug consequently has been available to the
field in varying administration forms and dosages, and the
preparation of such is therefore not considered necessary in this
description relating to a use for such drug. It is noted that this
drug is readily soluble, and its preparation in IV form is
therefore easily accomplished by usual techniques known to persons
skilled in the art.
It is interesting to note the currently perceived mechanism
associated at least in part with the shock condition. Although not
intended in any way as a limitation of the present invention, the
potential relationship with the operation of fenoprofen will be
discussed.
There is a recognized mechanism known as the protaglandin cascade
or arachidonic acid cascade which leads to the release of several
different compounds within the body. This cascade begins with the
presence of inaccessible phospholipids within the body. Upon
stimulus, these phospholipids convert to a form in which they are
accessible, and such conversion is believed to be inhibited by
glucocorticoids. Thus, certain glucocorticoids have been
investigated for counteracting the development of this cascade,
although with doubtful success as indicated earlier.
The accessible phospholipids are available to be acted upon by
phospholipase for conversion into arachidonic acid. This acid in
turn may yield several additional compounds along one of at least
two pathways. Conversion by lipoxygenase results in the production
of leukotrienes, 5,15 HPETE and 12-HPETE. Several other compounds
result from the operation of cyclo-oxygenase on the arachidonic
acid in the presence of oxygen to form PGG.sub.2, convertible in
turn to PGH.sub.2, prostacyclin, thromboxane A.sub.2, etc.
In the past, it has been considered to use inhibitors to the
cyclo-oxygenase pathway in shock. One such example is ibuprofen,
discussed earlier. However, the results have been typically
reported as improving hemodynamics, but not mortality.
Prior studies have demonstrated in a canine endotoxic shock model
(LD.sub.100) that the selective cyclo-oxygenase inhibitor,
ibuprofen, given 60 minutes after endotoxin administration, could
improve hemodynamics within 30-60 minutes, but did not improve
survival over control animals. Naloxone administration has
demonstrated only transient hemodynamic improvement. These and
other data suggest that the products of the prostaglandin cascade
are probably more hemodynamically important than the opioids as
vasoactive mediators in this type of canine endotoxic shock.
Leukotrienes, products of the lipoxygenase pathway, have also been
implicated as important vasoactive mediators in the endotoxic
(septic) shock syndrome. When given systemically, they can cause
hypotension, can increase vascular permeability, and can decrease
myocardial contractility which are characteristic features of
shock.
Many vasoactive mediators have been implicated in causing or
maintaining the hypotension in hemorrhagic shock. The present
invention utilizes fenoprofen, a selective cyclo-oxygenase
inhibitor, in the treatment of hemorrhagic shock, and in one aspect
has been examined particularly on a canine hemorrhagic shock
model.
After thiopental anesthesia, animals were instrumented to measure
various cardiovascular parameters. All animals were bled to and
maintained at a mean arterial pressure (MAP) of 60 mmHg for 90
minutes. After the shock period, animals were then given fenoprofen
(10 mg/kg) (n=9) or an equivalent volume of saline (n=6). After
another 90 minutes observation period, the shed blood was
reinfused. A significant increase of MAP was noted in the
fenoprofen group secondary to an increase of total peripheral
resistance (TPR).
In another aspect, the present invention includes the use of
fenoprofen, a selective cyclo-oxygenase inhibitor in the treatment
of endotoxic shock, and in one example demonstrates the use of
fenoprofen in the canine endotoxic shock model.
After thiopental anesthesia (25 mg/kg i.v.), animals were
instrumented to measure various cardiovascular parameters.
Endotoxic shock was induced by injecting E. coli (0111:B.sub.4)
endotoxic (1 mg/kg i.v.). Fenoprofen (1 mg/kg i.v.) (n=5),
fenoprofen (10 mg/kg) (n=6), or saline (n=12) was injected 60
minutes after endotoxin administration. During the treatment
period, both doses of fenoprofen increased mean arterial pressure,
dP/dt.sub.max, heart rate, and vascular resistance in a
dose-response manner over the control animals. Twenty-four hour
survival was 0% for the control animals (n=12), 60% for the
fenoprofen group (1 mg/kg) and 61% for the fenoprofen (10 mg/kg)
group. These data demonstrate that fenoprofen improves survival in
an otherwise lethal endotoxic shock model.
EXAMPLE I
Healthy, adult male beagles weighing 10-15 kg were anesthetized
with thiopental (25 mg/kg) i.v. two days prior to each experiment.
They were then shaved and depilated in the neck, mid-thorax, and
femoral areas and allowed to spontaneously recover. On the day of
the experiment, each dog was again anesthetized with thiopental (25
mg/kg i.v.), intubated with a cuffed endotracheal tube, and allowed
to breath spontaneously on room air. Additional small doses of
thiopental (1-2 mg/kg) were administered when necessary. On the
shaved areas, the impedance electrode tape was placed
circumferentially in the usual manner.
In the neck, the right jugular vein was exposed and a Swan-Ganz
catheter was inserted to measure mean pulmonary artery pressure
(PAP) and mean pulmonary artery wedge (PAW) pressure. Also through
the same neck approach, a "pigtail" catheter was inserted into the
left ventricle to measure dP/dt.sub.max.
In the left groin area, the femoral artery was exposed and a 7F
catheter was inserted and connected to a transducer to measure
arterial pressure (MAP). In the right groin area, the femoral
artery was exposed and a 7F catheter was inserted and connected to
a blood bag (Fenwal Laboratories, Deerfield, Ill.) for hemorrhaging
the animal. All pressures were measured with Gould-Statham P23Db
pressure transducers, which were calibrated daily.
Other cardiodynamics were measured by a Minnesota Impedance
Cardiograph (Model 304B) (Surcom, Inc., Minneapolis, MN) which is a
tetrapolar electrode system. The outer two leads (1 and 4) were
connected to an oscillator which produced a 100 kH, 4 ma constant
current and detected an EKG signal. The inner two electrodes were
connected to an Impedance Cardiograph Microcomputer (Model 700)
(Surcom, Inc., Minneapolis, MN) which measured on a beat-by-beat
basis, heart rate (HR), stroke volume (SV), cardiac output (CO),
and the Heather Index (HI) (a measurement of contractility). It has
been demonstrated in the past that CO measured by impedance is
equivalent to CO determined by the thermodilution or dye dilution
methods. Recent work has demonstrated a correlation coefficient of
r=0.88 for SV determined by impedance and thermodilution during the
pre-shock and shock periods of an endotoxin model.
Total peripheral resistance (TPR) was calculated from the following
formula: TPR:=MAP/CO. Pulmonary vascular resistance (PVR) was
calculated from the formula: PVR=PAP-PAW/CO. Ejection fraction (EF)
was calculated from a standard impedance signal using the method of
Judy which has been shown to be equivalent to single-pass
radionuclide or ventriculogram methods. End diastolic volume was
calculated as follows: EDV=SV/EF. All impedance data and pressures
were recorded simultaneously on a Beckman Type R Dynograph.
After all surgery was completed, each dog was given heparin (10,000
U i.v.). After a 15 minute baseline period, the animals were bled
to a MAP of 60 mmHg over a 30 minute period. This pressure was
maintained for another 60 minutes at this level by raising or
lowering the blood bag as needed.
After the 90 minutes of shock, the animals were given either
fenoprofen (10 mg/kg) (n=9) or an equal volume of saline (n=6)
intravenously. After another 90 minutes observation period, the
shed blood was reinfused in both groups and observed for another 45
minutes. After this last observation period, the catheters were
removed, the vessels ligated, and the animals were returned to
their cages. Animals were observed every 12 hours until death and
then autopsied.
STATISTICAL ANALYSIS
Data was analyzed using paired Student t-tests, two group Student
Fisher's exact test, and repeated measures analysis of variance. A
p-value of .ltoreq.0.05 was considered significant.
RESULTS
Analysis of data during the pre-shock and shock periods
demonstrated no significant statistical differences (p.ltoreq.0.05)
between the groups except for PAP and PVR in the hemorrhage period
for the fenoprofen group. Fenoprofen (10 mg/kg) given to
instrumented, non-shocked animals had no effect on hemodynamics.
FIG. 1 demonstrates the increase of MAP after fenoprofen
administration. There was no increase of HR, SV, CO, EDV, HI, or
dP/dt.sub.max to account for the increase of MAP (FIGS. 2-8). The
parameter which did increase to account for the increase of MAP was
TPR (FIG. 9). Even though PAP and PVR was elevated during the shock
period in the fenoprofen group, there was no increase after
fenoprofen administration. Survival at 48 hours was 50% (3/6) in
the control group and 100% (9/9) in the fenoprofen group (Table
1).
TABLE 1 ______________________________________ SURVIVAL TIME
CONTROL (n = 6) FENOPROFEN (n = 9)
______________________________________ 24 hours 3 9 48 hours 3 9
______________________________________
DISCUSSION
Recent work in shock research has implicated many circulating
vasoactive mediators as important contributors to the
pathophysiology of shock. The present study examined the effects of
a prostaglandin inhibitor on the hemodynamics of a prolonged
hemorrhagic shock model in dogs. The data demonstrated that
fenoprofen, a selective cyclo-oxygenase inhibitor, increased MAP
secondary to a rise of TPR. In summary, fenoprofen, a
cyclo-oxygenase inhibitor, increases hemodynamics in a hemorrhagic
shock model by increasing vascular resistance.
EXAMPLE II
Healthy adult male hounds weighing 20-25 kg were anesthetized with
thiopental (25 mg/kg) i.v. two days prior to each experiment. They
were then shaved and depilated in the neck, mid thorax, and femoral
areas, and allowed to spontaneously recover. On the day of the
experiment, each dog was again anesthetized with thiopental (25
mg/kg i.v.), intubated with a cuffed endotracheal tube, and allowed
to breath spontaneously on room air. Additional small doses of
thiopental (1-2 mg/kg) were administered when necessary. On the
shaved areas, the impedance electrode tape was placed
circumferentially in the usual manner.
In the neck, the right jugular vein was exposed and a Swan-Ganz
catheter was inserted to measure mean pulmonary artery pressure
(PAP) and mean pulmonary artery wedge (PAW) pressure. Also through
the same neck approach, a "pigtail" catheter was inserted into the
left ventricle to measure dP/dt.sub.max.
In the left groin area, the femoral artery was exposed and a 7F
catheter was inserted and connected to a transducer to measure mean
arterial pressure (MAP). All pressures were measured with
Gould-Statham P23Db pressure transducers which were calibrated
daily.
Other cardiodynamics were measured by a Minnesota Impedance
Cardiograph (Model 304B) (Surcom, Inc., Minneapolis, MN) which is a
tetrapolar electrode system. The outer two leads (1 and 4) were
connected to an oscillator which produced a 100 kHz, 4 ma constant
current and detected an EKG signal. The inner two electrodes were
connected to an Impedance Cardiograph Microcomputer (Model 7000)
(Surcom, Inc., Minneapolis, MN) which measured on a beat-by-beat
basis, heart rate (HR), stroke volume (SV), cardiac output (CO),
and Heather Index (HI) (a measurement of contractility). It has
been demonstrated in the past that CO measured by impedance is
equivalent to CO determined by the thermodilution or dye dilution
methods. Recent work has demonstrated a correlation coefficient of
r=0.88 for SV determined by impedance and thermodilution during the
pre-shock and shock periods for this LD.sub.100 canine endotoxic
shock model. Total peripheral resistance (TPR) was calculated by
the following formula: TPR=MAP/CO.
Ejection fraction (EF) was calculated from a standard impedance
signal using the method of Judy which has been shown to be
equivalent to single-pass radionuclide or ventriculogram methods.
End diastolic volume was calculated as follows: EDV=SV/EF.
All impedance data and pressures were recorded simultaneously on a
Beckman Type R Dynograph. After all surgery was completed, each dog
was given heparin (10,000 U i.v.). After a 30 minute baseline
period, each dog was given endotoxin (1 mg/kg i.v.) (E. coli
011:B4) (Difco). Sixty minutes after endotoxin administration,
fenoprofen (1 mg/kg), fenoprofen (10 mg/kg) or an equivalent volume
of saline was injected intravenously. Animals were physiologically
monitored for an additional 21/2 hours. The catheters were then
removed, and the animals were returned to their cages. Animals were
observed until death and then were autopsied.
STATISTICAL ANALYSIS
Data was analyzed using paired Student t-tests and repeated
measures analysis of variance. Mortality data was analyzed using
the Fisher's exact test. A p-value of .ltoreq.0.5 was considered
significant.
RESULTS
Comparison of the groups demonstrated no significant differences
for any of the parameters during the baseline and the shock periods
(FIGS. 10-20). No hemodynamic changes were noted when fenoprofen
was administered to instrumented non-shocked animals. At time 0,
endotoxic shock was induced by injecting endotoxin (E. coli
0111:B.sub.4) (1 mg/kg i.v.). Sixty minutes after endotoxin
administration, fenoprofen at two different doses or an equivalent
volume of saline was administered. FIGS. 10-20 illustrate the
typical hemodynamic profile after endotoxin administration for our
model. This consists of essentially three phases: (1) early, rapid
hypotension, (2) transient compensatory phase, (3) late
hypotension.
FIG. 10 demonstrates that both doses of fenoprofen were equally
effective in increasing MAP to near pre-shock levels. The group
given a lower dose of fenoprofen (1 mg/kg) demonstrated an increase
of CO and EDV late in the treatment period while the group given
the larger dose did not (FIGS. 11-15). These minor changes in CO
and EDV in the one group and no comparable changes in the group
given the larger dose of fenoprofen could not account for the
increase of MAP in both treatment groups. With regards to
contractility, there was a dose-response increase in dp/dt.sub.max
in the fenoprofen groups (FIG. 17). HI, the impedance contractility
index, demonstrated no improvement in either fenoprofen group (FIG.
16). The parameter with the most improvement to account for the
increase of MAP was TPR which was improved in a dose response
manner in the fenoprofen groups (FIG. 18).
Survival at 24 hours was 0% (0/12) for the control group, 60% (3/5)
for the fenoprofen (1 mg/kg) group, and 67% (4/6) for the
fenoprofen (10 mg/kg) group (Table II).
TABLE II ______________________________________ 24 HOUR SURVIVAL
CONTROL 0/12 p value ______________________________________
FENOPROFEN 1 mg/kg 3/5 .015 10 mg/kg 4/6 .005
______________________________________
DISCUSSION
The present study illustrates that the administration of
fenoprofen, a selective cyclo-oxygenase inhibitor, not only
improves hemodynamics, but also extends survival in an otherwise
lethal canine endotoxic shock model. Both doses of fenoprofen
increased MAP, dp/dx.sub.max, and vascular resistance (TPR and PVR)
in a dose-response manner. There were minor changes noted between
the two groups. The lower dose of fenoprofen demonstrated some
minor improvement of CO and EDV late in the treatment period. The
increase, however, could not account for the increase of MAP. The
major parameter increase to account for the increase of MAP in both
groups was vascular resistance. There was an increase of
dp/dt.sub.max in both treatment groups. However, HI, the impedance
contractility index, demonstrated no improvement. Since various
contractility indices can be affected by preload or afterload, one
cannot always accurately assess the true contractility
characteristics of the myocardium in pathologic states.
It has therefore been shown that the administration of fenoprofen
will effectively treat the shock condition when given in
therapeutic amounts. Fenoprofen is also appropriate for the
pretreatment of patients considered to have a high risk of
infection (e.g. surgery) or to prevent other types of potential
shock situations. Pretreatment is appropriate, for example, for
hospitalized patients, particularly for patients who have suffered
a significant loss of blood or have a potential for additional
blood loss, or having a high risk or potential for shock. In
particular, the administration of the drug desirably within an hour
or two before the onset of the shock condition improves
hemodynamics and increases the chances of survival from the shock
condition. A further example of a pretreatment situation would be
in the administration of fenoprofen to a person prior to the person
undergoing a surgical procedure, which would put the person at high
risk for severe blood loss or infection.
The fenoprofen may be administered in a variety of manners,
typically depending on the circumstances of administration. The
drug may for example be administered parenterally, and preferably
intravenously.
EXAMPLE III
Impedance cardiography and invasive methods were used to measure
various cardiovascular parameters. Dogs (beagles) were anesthetized
with thiopental (25 mg/kg i.v.), intubated, and allowed to breathe
spontaneously. Endotoxic shock was induced by injecting E. coli
(0111:B.sub.4) endotoxin (1 mg/kg i.v.). Fenoprofen (10 mg/kg)
(n=6) or saline (n=6) was injected 120 minutes after endotoxin
administration. Pre-shock and shock hemodynamics between the two
groups showed no significant differences. During the treatment
period, no differences between the two groups were noted for heart
rate, stroke volume, cardiac output (CO), end diastolic volume,
dP/dt, and pulmonary artery wedge pressure. However, in the
fenoprofen group, there was a sustained improvement in mean
arterial pressure (MAP) and total peripheral resistance (TPR).
Representative data (mean+/-SEM) observed two hours after drug
administration are listed in Table III. Twenty-four hour survival
for the control group was 0% (0/6) versus 100% (6/6) for the
fenoprofen group.
TABLE III ______________________________________ Control Fenoprofen
______________________________________ MAP 77.4 +/- 7.9 150 +/-
4.5* CO 3.37 +/- 0.46 2.30 +/- 0.38 TPR 24.8 +/- 4.2 76.6 +/- 16.9*
______________________________________ *p .ltoreq. 0.05
These data indicate that delayed intervention (two hours) with
fenoprofen can still improve survival in an otherwise LD.sub.100
endotoxic shock model.
* * * * *